Interpretive Summary: Type 2 diabetes (T2D) has profound effects on metabolism that can be detected in plasma. While increases in circulating non-esterified fatty acids (NEFA) are well described in T2D, effects on circulating signaling lipids have received little attention. Oxylipins and endocannabinoids are classes of fatty acid metabolites with many structural members. These bioactive lipid classes influence insulin signaling, adipose function and inflammation by autocrine mechanisms (i.e. being produced within affected cells), paracrine mechanisms (i.e. being produced by neighboring cells), or endocrine mechanisms (i.e. being produced by tissues remote to the affected cells). To link T2D-dependent changes in plasma NEFA and signaling lipids, we quantitatively targeted >150 of these plasma lipids in age-and body mass index-matched, overweight to obese African-American women with and without T2D. Diabetic NEFA patterns indicate increases in steroyl-CoA desaturase activity and decreases in very long chain polyunsaturated fatty acid chain shortening, consistent with patterns observed during development of nonalcoholic fatty liver disease, a “silent” disease characterized by liver fat accumulation that can lead to inflammation that can permanently damage the liver. Further, epoxides and ketones of eighteen carbon polyunsaturated fatty acids were elevated by T2D and were strongly correlated with changes in NEFA, consistent with their liberation during adipose lipolysis. Endocannabinoid behavior differed by class. While monoacylaglycerides reflect subject body mass, diabetes increased an array of putatively anti-inflammatory N-acylethanolamides that were positively correlated with increases in pro-inflammatory 5-lipooxygenase products. These results link changes in the circulating lipid metabolites to biochemical alterations associated with the T2D state.

Technical Abstract:
Type 2 diabetes (T2D) has profound effects on metabolism that can be detected in plasma. While increases in circulating non-esterified fatty acids (NEFA) are well described in T2D, effects on circulating signaling lipids have received little attention. Oxylipins and endocannabinoids are classes of fatty acid metabolites with many structural members. These bioactive lipid classes influence insulin signaling, adipose function and inflammation through autocrine, paracrine and endocrine mechanisms. To link T2D-dependent changes in plasma NEFA and signaling lipids, we quantitatively targeted >150 plasma lipidome components in age and body mass index matched, overweight to obese, non-diabetic and T2D African-American women. Diabetic NEFA patterns indicate increases in steroyl-CoA desaturase activity and decreases in very long chain polyunsaturated fatty acid chain shortening. Further, epoxides and ketones of eighteen carbon polyunsaturated fatty acids were elevated by T2D and strongly correlated with changes in NEFA, consistent with their liberation during adipose lipolysis. Endocannabinoid behavior differed by class. While monoacylaglycerides reflect subject body mass, diabetes increased an array of N-acylethanolamides that were positively correlated with increases in pro-inflammatory 5-lipooxygenase products. These results link changes in the circulating lipidome to biochemical alterations associated with the T2D state.